The intent of the Wistar/Penn SPORE in Skin Cancer is to decrease the morbidity and mortality of skin cancers through improved understanding of the pathogenesis of these diseases using novel, validated molecular biomarkers of risk, progression and prognosis and the development of targeted therapies. This SPORE is focused on major skin cancers: melanoma, cutaneous T cell lymphoma (CTCL) and squamous cell carcinoma (SCC). The overall goals of this SPORE are to address five translationally important areas: 1) Risk assessment. We will test the hypothesis that susceptibility to melanoma stems from complex interactions of multiple factors, including inherited genotypes, environmental exposures, and endogenous pigmentation (Projects 1 and 2). 2) Risk prediction. Genotypes (Projects 1 and 2) will be integrated with existing risk factors to develop prediction models of individual melanoma risk. These models will be important in stratifying individuals for screening and prevention, and to enhance the efficacy of targeted prevention trials. 3) Prognosis. Using data from Projects 1 (alterations in DNA), and 2 and 3 (differences in protein levels) we will develop and externally validate comprehensive, biologically based prognostic models that will be used in clinical trials and in patient management. 4) Diagnosis. We will develop and validate biomarkers to distinguish melanoma in situ from invasive and/or tumorigenic melanoma (Project 3). 5) Therapy. We will investigate several novel therapies for advanced melanoma and CTCL (Projects 4, 5 and 6). These include: a) targeted therapy for melanoma: molecular targeting of MAP kinase signaling pathways capitalizing on the recent discovery that the majority of human melanomas have an activating mutation in BRAF (Project 6); b) cytokine therapy of CTCL: determination of the mechanisms whereby CTCL becomes refractory to recombinant human IL-12-based therapies and how therapeutic efficacy can be enhanced by cytokines, including IL-2 (Project 5); and c) active and passive immunotherapy of melanoma with lymphocytes and defined tumor antigens: an organotypic model of melanoma will define new cytotoxic T-cell specificities against human melanoma, leading to the identification of novel antigens for vaccine trials and "optimized" adoptive immunotherapy (Project 4). The Wistar/Penn SPORE addresses the most aggressive cancers of the skin. It is focused on melanoma because of its rising incidence and significant potential for lethality. It is the subject of five of the six Projects and three of the five Pilot Studies. CTCL is addressed in one Project and one Pilot Study, and SCC in one Pilot Study. This endeavor represents the synergistic integration of well-established individual research programs towards our collective goals.